Cancer is a major health problem across the globe. Current treatments generally involve surgery, radiation therapy (radiotherapy), chemotherapy, or a combination of these approaches, each of which has limitations. There remains a need for new and improved cancer therapies, including combination therapies.
It is estimated that approximately two thirds of cancer patients receive radiotherapy, which involves the application of ionizing radiation as part of a treatment to control or kill malignant cells. Ionizing radiation is used to damage the DNA of exposed tissue leading to cell death. Radiotherapy may be curative in a number of types of cancer. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgical removal. Radiotherapy may be synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. Many common cancer types can be treated with radiation therapy in some way. The precise treatment intent will depend on the tumor type, location, stage, and health of the patient. Radiotherapy also has applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification.
Exposure of living cells to ionizing radiation leads to biological damage by both direct and indirect interactions with cell components, mainly DNA. The direct action of radiation, e.g. direct energy deposited in the DNA, accounts for only a small fraction of the energy deposited into the biological system. The cell contains 70-80% water. It is known that the contribution of free radicals, via radiolysis of water, to biological damage far exceeds that of direct action in ionizing radiation, by orders of magnitude.
Different cancers respond differently to radiotherapy. The response of a cancer to radiation is described by its radiosensitivity. Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation. These include leukemias, most lymphomas and germ cell tumors. Most of the epithelial cancers are only moderately radiosensitive, and require a significantly higher dose of radiation (60-70 Gy) to achieve a radical cure. Some types of cancer, such as renal cell cancer and melanoma, are highly radioresistant and cannot be cured by radiation doses that are safe in clinical practice. The response of a tumor to radiotherapy is also related to its size and conditions. For complex reasons, very large tumors respond less well to radiation than smaller tumors or microscopic disease. One technique to enhance the radiosensitivity of a cancer is by giving a radiosensitizing drug (a so-called “radiosensitizer”) during a course of radiotherapy.
Radiotherapy itself is painless, but it can cause serious side effects. Particularly high doses can cause varying side effects, including acute side effects happening in the months following treatment, long-term side effects in years following treatment, and cumulative side effects after re-treatment. The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and the patient. Acute side effects include fatigue and skin irritation, nausea and vomiting, damage to the epithelial surfaces, mouth, throat and stomach sores, intestinal discomfort, swelling (edema) and infertility. In clinical oncology, efforts are made to use low radiation doses to reduce toxic side effects, e.g., by use of a radiosensitizer to enhance the treatment efficacy.
Cisplatin (cis-Pt(NH3)2Cl2) is a platinum-based antineoplastic drug and is one of the most widely used drugs for cancer treatment. Cisplatin has also been used as a radiosensitizer to enhance the radiosensitivity of the cancer during radiotherapy [Rose et al., 1999]. Despite its widespread use, cisplatin has two major drawbacks: severe toxic side effects and both intrinsic and acquired resistance. These drawbacks even led to the calling of terminating the clinical applications of the heavy-metal Pt-based anticancer drugs [Reese, 1995]. There remains a need to identify less toxic analogues and to develop combination therapies, including chemo-radiotherapies, that reduce cisplatin toxicity and prevent or overcome drug resistance.
While a variety of chemotherapeutic agents have been combined with radiotherapy, nearly all are toxic. Chemotherapeutic agents generally cause significant, and often dangerous, side effects. Side effects associated with chemotherapeutic agents are generally the major factor in defining a dose-limiting toxicity (DLT) for the agent.
WO/2011/026219 (to the present inventor), entitled Combination Therapy for Cancer Comprising a Platinum-Based Antineoplastic Agent and a Biocompatible Electron Donor, there is disclosed a combination chemotherapy of cisplatin with an electron-donating agent to enhance the anti-cancer efficacy of cisplatin (also see, Lu, 2011).